CN115304507A - Synthesis method of N-substituted aryl formamide - Google Patents
Synthesis method of N-substituted aryl formamide Download PDFInfo
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- CN115304507A CN115304507A CN202211139676.XA CN202211139676A CN115304507A CN 115304507 A CN115304507 A CN 115304507A CN 202211139676 A CN202211139676 A CN 202211139676A CN 115304507 A CN115304507 A CN 115304507A
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- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000004440 column chromatography Methods 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 28
- 238000010791 quenching Methods 0.000 claims abstract description 23
- 239000000758 substrate Substances 0.000 claims abstract description 22
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 230000000171 quenching effect Effects 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 114
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 93
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 42
- 230000015572 biosynthetic process Effects 0.000 claims description 36
- 238000003786 synthesis reaction Methods 0.000 claims description 36
- CKRZKMFTZCFYGB-UHFFFAOYSA-N N-phenylhydroxylamine Chemical compound ONC1=CC=CC=C1 CKRZKMFTZCFYGB-UHFFFAOYSA-N 0.000 claims description 26
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 21
- 239000001431 2-methylbenzaldehyde Substances 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 claims description 10
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- VVQDMDRAUXFEND-UHFFFAOYSA-N n-(4-chlorophenyl)hydroxylamine Chemical compound ONC1=CC=C(Cl)C=C1 VVQDMDRAUXFEND-UHFFFAOYSA-N 0.000 claims description 9
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 8
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 5
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 claims description 5
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 claims description 5
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 claims description 5
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 claims description 4
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 claims description 4
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 claims description 4
- QITLDCYUPWIQCI-UHFFFAOYSA-N n-(3-methylphenyl)hydroxylamine Chemical compound CC1=CC=CC(NO)=C1 QITLDCYUPWIQCI-UHFFFAOYSA-N 0.000 claims description 4
- FFGRMJZVLLBFCR-UHFFFAOYSA-N n-(4-bromophenyl)hydroxylamine Chemical compound ONC1=CC=C(Br)C=C1 FFGRMJZVLLBFCR-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
- 235000003270 potassium fluoride Nutrition 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 216
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 108
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 60
- 239000003208 petroleum Substances 0.000 description 38
- 239000012074 organic phase Substances 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 238000000605 extraction Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 15
- ZVSKZLHKADLHSD-UHFFFAOYSA-N benzanilide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=CC=C1 ZVSKZLHKADLHSD-UHFFFAOYSA-N 0.000 description 14
- 150000001408 amides Chemical class 0.000 description 5
- -1 amide compounds Chemical class 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- KKBYMZGIRNZAOT-UHFFFAOYSA-N 2-chloro-n-(4-chlorophenyl)benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC=CC=C1Cl KKBYMZGIRNZAOT-UHFFFAOYSA-N 0.000 description 2
- AXQVIWHAEYLGLO-UHFFFAOYSA-N 2-chloro-n-phenylbenzamide Chemical compound ClC1=CC=CC=C1C(=O)NC1=CC=CC=C1 AXQVIWHAEYLGLO-UHFFFAOYSA-N 0.000 description 2
- RNFCQIOHQPIUOI-UHFFFAOYSA-N 2-nitro-n-phenylbenzamide Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)NC1=CC=CC=C1 RNFCQIOHQPIUOI-UHFFFAOYSA-N 0.000 description 2
- QDIUKUHOHYCIRM-UHFFFAOYSA-N 3-chloro-n-phenylbenzamide Chemical compound ClC1=CC=CC(C(=O)NC=2C=CC=CC=2)=C1 QDIUKUHOHYCIRM-UHFFFAOYSA-N 0.000 description 2
- OAAVWHUTJIJKOU-UHFFFAOYSA-N 3-methoxy-n-phenylbenzamide Chemical compound COC1=CC=CC(C(=O)NC=2C=CC=CC=2)=C1 OAAVWHUTJIJKOU-UHFFFAOYSA-N 0.000 description 2
- CRWYLZLIZQKHMM-UHFFFAOYSA-N 3-methyl-n-(4-methylphenyl)benzamide Chemical compound C1=CC(C)=CC=C1NC(=O)C1=CC=CC(C)=C1 CRWYLZLIZQKHMM-UHFFFAOYSA-N 0.000 description 2
- DUSYVXRZSXLXRH-UHFFFAOYSA-N 3-methyl-n-phenylbenzamide Chemical compound CC1=CC=CC(C(=O)NC=2C=CC=CC=2)=C1 DUSYVXRZSXLXRH-UHFFFAOYSA-N 0.000 description 2
- WXARQXZZFOCDNR-UHFFFAOYSA-N 4-chloro-n-(4-chlorophenyl)benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 WXARQXZZFOCDNR-UHFFFAOYSA-N 0.000 description 2
- SFHDVPIEJXCMBP-UHFFFAOYSA-N 4-chloro-n-phenylbenzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)NC1=CC=CC=C1 SFHDVPIEJXCMBP-UHFFFAOYSA-N 0.000 description 2
- XOJAJRFBOKCXPI-UHFFFAOYSA-N 4-methoxy-n-phenylbenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1 XOJAJRFBOKCXPI-UHFFFAOYSA-N 0.000 description 2
- PQEOPHYIUYAVDQ-UHFFFAOYSA-N 4-methyl-n-phenylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=CC=C1 PQEOPHYIUYAVDQ-UHFFFAOYSA-N 0.000 description 2
- MZNCVTCEYXDDIS-UHFFFAOYSA-N Mebenil Chemical compound CC1=CC=CC=C1C(=O)NC1=CC=CC=C1 MZNCVTCEYXDDIS-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- XFPYCMXNXPPZRV-UHFFFAOYSA-N ethyl 4-benzamidobenzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NC(=O)C1=CC=CC=C1 XFPYCMXNXPPZRV-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- PDEGMQCBLXQVLD-UHFFFAOYSA-N n-(3-methylphenyl)benzamide Chemical compound CC1=CC=CC(NC(=O)C=2C=CC=CC=2)=C1 PDEGMQCBLXQVLD-UHFFFAOYSA-N 0.000 description 2
- RAVWHRINPHQUMU-UHFFFAOYSA-N n-(4-bromophenyl)benzamide Chemical compound C1=CC(Br)=CC=C1NC(=O)C1=CC=CC=C1 RAVWHRINPHQUMU-UHFFFAOYSA-N 0.000 description 2
- GTAAHWPBBMVBRJ-UHFFFAOYSA-N n-(4-chlorophenyl)-2-methylbenzamide Chemical compound CC1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 GTAAHWPBBMVBRJ-UHFFFAOYSA-N 0.000 description 2
- WQWILBQLOABMSN-UHFFFAOYSA-N n-(4-chlorophenyl)-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(Cl)C=C1 WQWILBQLOABMSN-UHFFFAOYSA-N 0.000 description 2
- PJFPJLMLHHTWDZ-UHFFFAOYSA-N n-(4-chlorophenyl)benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC=CC=C1 PJFPJLMLHHTWDZ-UHFFFAOYSA-N 0.000 description 2
- YUIHXKGKVSVIEL-UHFFFAOYSA-N n-(4-methylphenyl)benzamide Chemical compound C1=CC(C)=CC=C1NC(=O)C1=CC=CC=C1 YUIHXKGKVSVIEL-UHFFFAOYSA-N 0.000 description 2
- AGJOAIMUXIQLCN-UHFFFAOYSA-N n-(4-methylphenyl)hydroxylamine Chemical compound CC1=CC=C(NO)C=C1 AGJOAIMUXIQLCN-UHFFFAOYSA-N 0.000 description 2
- CIPHTOQKGSLCLV-UHFFFAOYSA-N n-phenylnaphthalene-1-carboxamide Chemical compound C=1C=CC2=CC=CC=C2C=1C(=O)NC1=CC=CC=C1 CIPHTOQKGSLCLV-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- HFIVLLBFACNAFN-UHFFFAOYSA-N [1-amino-2-[2-(4-methoxyphenyl)ethylamino]ethyl]phosphonic acid Chemical compound COc1ccc(CCNCC(N)P(O)(O)=O)cc1 HFIVLLBFACNAFN-UHFFFAOYSA-N 0.000 description 1
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- WTIQBXJYUKTCPO-UHFFFAOYSA-N ethyl 4-(hydroxyamino)benzoate Chemical compound CCOC(=O)C1=CC=C(NO)C=C1 WTIQBXJYUKTCPO-UHFFFAOYSA-N 0.000 description 1
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 150000002843 nonmetals Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- FODWRUPJCKASBN-UHFFFAOYSA-M tetrabutylazanium;chloride;hydrate Chemical compound O.[Cl-].CCCC[N+](CCCC)(CCCC)CCCC FODWRUPJCKASBN-UHFFFAOYSA-M 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of N-substituted aryl formamide, which is characterized in that substrate aromatic aldehyde and hydroxylamine are dissolved in a solvent A, stirred overnight at room temperature, and the solvent A is evaporated; and adding an accelerator, alkali and a solvent B into the mixture, stirring the mixture at room temperature for reaction for 2 to 46 hours, adding a 1N HCl solution into the mixture for quenching reaction, and finally sequentially extracting, drying, filtering, concentrating and carrying out column chromatography separation to obtain the target product N-substituted aryl formamide. The method has the advantages of mild reaction conditions, simple operation, cheap and easily-obtained substrate, good atom economy, wide substrate application range and the like.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthetic method of N-substituted aryl formamide.
Background
Amides are one of the most important functional groups in organic chemistry, while amides have a wide range of uses in the fields of organisms, natural products, organic materials and medicine. According to statistics, in the first 200 small molecule drugs retail in 2020, more than 60% of drugs containing amide frameworks are available; in addition, about 16% of reactions in the drug synthesis process involve the formation of amide bond, and therefore, the synthesis method of amide compounds has been a hot problem for organic chemists to study.
The traditional synthesis method of amide compounds is based on the condensation of amine and carboxylic acid and its derivatives such as acyl chloride and acid anhydride, however, such method requires stoichiometric amount of accelerator, and usually generates a large amount of waste, and has poor atom economy and no environmental friendliness. Direct transition metal such as rhodium, ruthenium and manganese catalyzed reaction taking aldehyde and amine as substrates is appeared, and a brand new way (such as a reaction formula A) is provided for the synthesis of amide compounds, and the method avoids the defects of condensation reaction, but needs to add transition metal. In recent years, non-metals such asNThe method for synthesizing the amide by taking the aldehyde as the raw material, which is promoted by heterocyclic carbene, molecular iodine, iodobenzene acetate and the like, is also generated successively (such as the reaction formula A). Recently, a method for generating amide from aldehyde and nitrobenzene under double catalysis of light and metal has been reported, which avoids the use of an oxidizing agent, but requires a metal compound ferric chloride hexahydrate and a light source LED lamp (as in reaction formula B).
Therefore, it is especially necessary to find a synthetic method with simple reaction, simple operation and high yield.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of N-substituted aryl formamide with mild reaction conditions and no metal participation.
In order to solve the above problems, the synthesis method of N-substituted aryl formamide of the present invention is characterized in that: dissolving substrate aromatic aldehyde and hydroxylamine in a solvent A, stirring overnight at room temperature, and distilling off the solvent A; adding an accelerator, alkali and a solvent B into the mixture, stirring the mixture at room temperature for reaction for 2 to 46 hours, adding a 1N HCl solution into the mixture for quenching reaction, and finally sequentially extracting, drying, filtering, concentrating and carrying out column chromatography separation to obtain the compound with the structural formula shown in the specification
The target product of (1) is an N-substituted aryl formamide; wherein: r 1 Is any one functional group of hydrogen, chlorine, methyl, methoxyl, nitryl, trifluoromethyl and cyano, R 2 Is any one functional group of hydrogen, chlorine, methyl, ester group, carbonyl, bromine and fluorine; the molar ratio of the aromatic aldehyde to the hydroxylamine to the accelerator to the alkali is 1:1 to 1.2:0.5 to 1.5:0.5 to 1.5.
The aromatic aldehyde is one of benzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 2-nitrobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-methoxybenzaldehyde, 3-methylbenzaldehyde, 2-methylbenzaldehyde, 4-methylbenzaldehyde and 1-naphthaldehyde.
The hydroxylamine is one of N-phenylhydroxylamine, 4-chlorphenylhydroxylamine, 3-methylphenylhydroxylamine, 4-bromophenylhydroxylamine and 4-ethylhydroxylamine-benzoate.
The solvent A is any one of chloralkane solvent, alcohol and ether solvent.
The chloralkane solvent is any one of chloroform, dichloromethane and carbon tetrachloride.
The alcohol solvent is any one of methanol, ethanol and isopropanol.
The ether solvent is any one of diethyl ether, tetrahydrofuran and 1,4-dioxane.
The accelerant is any one of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, cesium fluoride and potassium fluoride.
The alkali is any one of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, DMAP and DBU.
The solvent B refers to a nitrile solvent.
Compared with the prior art, the invention has the following advantages:
1. the invention takes the aromatic aldehyde which is sold in the market and is easy to obtain as the substrate, and the cheap accelerant and the alkali react in the nitrile solvent at room temperature, thus the N-substituted aryl formamide compound can be generated with high yield.
2. The method is a one-step room temperature reaction, and has no transition metal catalysis or no photocatalysis, so that the method has the advantages of mild reaction conditions, simplicity in operation, cheap and easily available substrates, good atomic economy, wide substrate application range and the like.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a drawing showing a representative compound 3e of the present invention 1 H NMR chart.
FIG. 2 is a schematic representation of a representative compound 3e of the present invention 13 C NMR chart.
FIG. 3 is a drawing showing a representative compound 3n of the present invention 1 H NMR chart.
FIG. 4 is a schematic representation of a representative compound 3n of the present invention 13 C NMR chart.
FIG. 5 is a drawing showing 3v which is a representative compound of the present invention 1 H NMR chart.
FIG. 6 is a drawing showing 3v which is a representative compound of the present invention 13 C NMR chart.
Detailed Description
A synthetic method of N-substituted aryl formamide, said method comprises dissolving aromatic aldehyde and hydroxylamine of substrate in solvent A, stir overnight at room temperature, evaporate solvent A; then adding an accelerator, alkali and a solvent B into the mixture, stirring the mixture at room temperature for reaction for 2 to 46 hours, and adding 1NQuenching with HCl solution, extracting with ethyl acetate for 3~5 times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and separating with petroleum ether-ethyl acetate column chromatography to obtain the final product with structural formula
The target product of (1) is an N-substituted aryl formamide; wherein: r 1 Is any one functional group of hydrogen, chlorine, methyl, methoxy, nitro, trifluoromethyl and cyano, R 2 Is any one functional group of hydrogen, chlorine, methyl, ester group, carbonyl, bromine and fluorine; the molar ratio of the aromatic aldehyde to the hydroxylamine to the accelerator to the base is 1:1 to 1.2:0.5 to 1.5:0.5 to 1.5.
The reaction equation is as follows:
wherein: the aromatic aldehyde is one of benzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 2-nitrobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-methoxybenzaldehyde, 3-methylbenzaldehyde, 2-methylbenzaldehyde, 4-methylbenzaldehyde and 1-naphthaldehyde.
The hydroxylamine is one of N-phenylhydroxylamine, 4-chlorophenylhydroxylamine, 3-methylphenylhydroxylamine, 4-bromophenylhydroxylamine and 4-ethylhydroxylamine-benzoate.
The solvent A is any one of chloroalkane solvent, alcohol and ether solvent. The chloralkane solvent is any one of chloroform, dichloromethane and carbon tetrachloride. The alcohol solvent is any one of methanol, ethanol and isopropanol. The ether solvent is any one of diethyl ether, tetrahydrofuran and 1,4-dioxane.
The promoter is any one of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, cesium fluoride and potassium fluoride.
The alkali is any one of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, DMAP and DBU.
Solvent B is a nitrile solvent, such as any one of acetonitrile, propionitrile and butyronitrile.
The volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate column chromatography is 5 to 20:1.
the target product obtained is preferably 3a: r 1 =H，R 2 =H；3b：R 1 =4-Cl，R 2 =H；3c：R 1 =4-OCH 3 ，R 2 =H；3d：R 1 =2-NO 2 ，R 2 =H；3e：R 1 =3-Cl，R 2 =H；3f：R 1 =H，R 2 =4-Cl；3g：R 1 =H，R 2 =3-CH 3 ；3h：R 1 =H，R 2 =4-CH 3 ；3i：R 1 =H，R 2 =4-COOC 2 H 5 ；3j：R 1 =H，R 2 =4-Br；3k：R 1 =2-Cl，R 2 =4-Cl；3l：R 1 =4-Cl，R 2 =4-Cl；3m：R 1 =4-CF 3 ，R 2 =4-CH 3 ；3n：R 1 =4-CF 3 ，R 2 =4-Cl；3o：R 1 =3-OCH 3 ，R 2 =H；3p：R 1 =3-CH 3 ，R 2 =4-CH 3 ；3q：R 1 =2-CH 3 ，R 2 =4-Cl；3r：R 1 =2-CH 3 ，R 2 =H；3s：R 1 =4-CH 3 ，R 2 =H；3t：R 1 =3-CH 3 ，R 2 =H；3u：R 1 =2-Cl，R 2 =H；3v：R 1 =naphthyl，R 2 =H；3w：R 1 =4-CH 3 ，R 2 =4-Cl。
Example 1 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent is distilled off, tetrabutylammonium fluoride trihydrate (0.18 mmol, 0.057 g, 0.5 equiv.), potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) are added thereto, after stirring reaction for 3 hours at room temperature, 1N HCl solution is added for reaction, extraction is carried out again for 3 times with ethyl acetate, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 43% yield.
Example 2 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent is distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) and potassium hydroxide (0.18 mmol, 0. 0.010 g, 0.5 equiv.) and acetonitrile (2.0 mL) are added thereto, after stirring reaction for 3 hours at room temperature, 1N HCl solution is added for reaction, then ethyl acetate is added for extraction for 3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 51% yield.
Example 3a method for synthesizing N-phenylbenzamide 3a: the method comprises the steps of mixing the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) andNphenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) was dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.), lithium hydroxide (0.36 mmol, 0.0087 g, 1 equiv.) and acetonitrile (2.0 mL) were added thereto, stirred at room temperature for 10 hours, 1N HCl solution was added to quench the reaction, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 21% yield.
Example 4 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent is distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) and sodium hydroxide (0.36 mmol, 0.014 g, 1 equiv.) and acetonitrile (2.0 mL) are added thereto, stirred at room temperature for 3 hours, then 1N HCl solution is added to quench the reaction, then ethyl acetate is used for extraction for 3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 71% yield.
Example 5 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent is evaporated, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) potassium carbonate (0.36 mmol, 0.050 g, 1 equiv.) and acetonitrile (2.0 mL) are added thereto, stirred at room temperature for 3 hours, then 1N HCl solution is added for reaction, then ethyl acetate is used for extraction 3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 55% yield.
Example 6 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent is distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) and 4-dimethylaminopyridine (0.36 mmol, 0.044 g, 1 equiv.) and acetonitrile (2.0 mL) are added, stirred at room temperature for 7 hours, 1N HCl solution is added to quench the reaction, then ethyl acetate is added for 3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 27% yield.
Example 7 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent is distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.), 1,8-diazabicycloundecen-7-ene (0.36 mmol, 0.055 g, 1 equiv.) and acetonitrile (2.0 mL) are added thereto, after stirring reaction for 40 hours at room temperature, HCl 1N solution is added to quench the reaction, extraction is carried out 3 times with ethyl acetate, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 33% yield.
Example 8 a method of synthesizing N-phenylbenzamide 3a: the method is that substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent is evaporated, tetrabutylammonium bromide (0.36 mmol, 0.12 g, 1 equiv.), potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) are added, stirred at room temperature for 46 hours, then 1N HCl solution is added to quench the reaction, then ethyl acetate is used for 3 times extraction, the organic phases are combined, dried with anhydrous, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 71% yield.
Example 9 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent is distilled off, tetrabutylammonium chloride monohydrate (0.36 mmol, 0.11 g, 1 equiv.), potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) are added, stirred at room temperature for 46 hours, 1N HCl solution is added to quench the reaction, then ethyl acetate is used for extraction for 3 times, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 46% yield.
Example 10 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent is distilled off, tetrabutylammonium iodide (0.36 mmol, 0.13 g, 1 equiv.) and potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) are added, stirred at room temperature for 31 hours, 1N HCl solution is added to quench the reaction, then ethyl acetate is used for extraction for 3 times, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 25% yield.
Example 11 a process for the synthesis of N-phenylbenzamide 3a, which comprises dissolving the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) in dichloromethane (2.0 mL), stirring overnight at room temperature, distilling off the solvent, adding cesium fluoride (0.36 mmol, 0.055 g, 1 equiv.), potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL), stirring at room temperature for 18 hours, adding 1N HCl solution and quenching, extracting 3 times with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 33% yield.
Example 12 a method of synthesizing N-phenylbenzamide 3a: the method is that the substrates benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) are dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent is evaporated, potassium fluoride (0.36 mmol, 0.021 g, 1 equiv.) and potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) are added, stirred at room temperature for 46 hours, then 1N HCl solution is added to quench the reaction, then ethyl acetate is used for extraction for 3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave the desired product 3a in 14% yield.
Example 13 synthesis of N-phenylbenzamide 3a: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added sequentially, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added sequentially, after stirring at room temperature for 2 hours, the reaction was quenched with 1N HCl solution, extracted 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography gave N-phenylbenzamide in 76% yield.
1 H NMR (600 MHz, CDCl 3 ) δ 7.87 (d, J = 7.2 Hz, 3H), 7.65 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H).
13 C NMR (151 MHz, CDCl 3 ) δ 165.7, 137.9, 135.0, 131.8, 129.1, 128.8, 127.0, 124.6, 120.2.
Examples 1 to 13 illustrate the effect of different molar ratios, different bases, different quaternary ammonium salts, different fluorine salts on the reaction yield.
Example 14 synthesis of 4-chloro-N-phenylbenzamide 3 b: 4-chlorobenzaldehyde (0.36 mmol, 0.051 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in this order, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added, after stirring at room temperature for 2 hours, the reaction was quenched with 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =15 column chromatography, obtaining 4-chloro-N-phenylbenzamide, yield 84%.
1 H NMR (500 MHz, CDCl 3 ) δ 7.82 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.17 (t, J = 7.0 Hz, 1H).
13 C NMR (126 MHz, CDCl 3 ) δ 164.6, 138.2, 137.6, 133.3, 129.2, 129.1, 128.5, 124.8, 120.2.
Example 15 synthesis of 4-methoxy-N-phenylbenzamide 3 c: 4-methoxybenzaldehyde (0.36 mmol, 0.049 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in this order, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added, after stirring at room temperature for 3 hours, the reaction was quenched with 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave 4-methoxy-N-phenylbenzamide in 65% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.84 (d, J = 8.5 Hz, 2H), 7.79 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 165.2, 162.5, 138.1, 129.1, 128.9, 127.1, 124.3, 120.1, 114.0, 55.5.
Example 16 synthesis of 2-nitro-N-phenylbenzamide 3 d: dissolving 2-nitrobenzaldehyde (0.36 mmol, 0.054 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) in dichloromethane (2.0 mL), stirring overnight at room temperature, distilling off the solvent, adding tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) in sequence, quenching the reaction with potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL), stirring at room temperature for 5 hours, adding 1N HCl solution, extracting with ethyl acetate 3 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, petroleum ether: ethyl acetate =5:1 column chromatography gave 2-nitro-N-phenylbenzamide in 68% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 8.07 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.61-7.52 (m, 4H), 7.35 (t, J = 8.0 Hz, 2H), 7.17 (t, J= 7.5 Hz, 1H).
13 C NMR (126 MHz, CDCl 3 ) δ 164.5, 146.2, 137.3, 133.9, 132.8, 130.7, 129.3, 129.1, 128.6, 125.2, 124.7, 122.4, 120.5.
Example 17 synthesis of 3-chloro-N-phenylbenzamide 3 e: 3-chlorobenzaldehyde (0.36 mmol, 0.051 g, 1 equiv.) and N-phenylhydroxylamine (0.36 mmol, 0.039 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in this order, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added, after stirring at room temperature for 5 hours, the reaction was quenched with 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =15 column chromatography 1 gave 3-chloro-N-phenylbenzamide in 81% yield.
Of Compound 3e 1 H NMR and 13 c NMR is shown in FIG. 1~2.
1 H NMR (500 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.41-7.35 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H).
13 C NMR (126 MHz, CDCl 3 ) δ 164.5, 137.6, 136.7, 134.9, 131.8, 130.1, 129.1, 127.4, 125.1, 124.9, 120.4.
Example 18 Synthesis of N- (4-chlorophenyl) benzamide 3 f: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.36 mmol, 0.052 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in this order, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added, after stirring for 6 hours at room temperature, 1N HCl solution was added to quench the reaction, followed by extraction with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =15 column chromatography 1 gave N- (4-chlorophenyl) benzamide in 82% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.86 (d, J = 7.0 Hz, 2H), 7.81 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H).
13 C NMR (126 MHz, CDCl 3 ) δ 165.7, 136.5, 134.6, 132.1, 129.6, 129.1, 128.9, 127.0, 121.4.
Example 19 synthesis of N- (3-methylphenyl) benzamide 3 g: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N- (3-methylphenyl) hydroxylamine (0.36 mmol, 0.044 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was evaporated off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added sequentially, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were stirred for 3 hours at room temperature, 1N HCl solution was added to quench the reaction, followed by extraction with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =19 column chromatography 1 gave N- (3-methylphenyl) benzamide in 63% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.86 (d, J = 7.5 Hz, 2H), 7.81 (s, 1H), 7.56-7.46 (m, 4H), 7.41 (d, J = 7.5 Hz, 1H), 7.25-7.23 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 2.36 (s, 3H).
13 C NMR (126 MHz, CDCl 3 ) δ 165.7, 139.1, 137.9, 135.1, 131.8, 128.9, 128.8, 127.0, 125.4, 120.9, 117.3, 21.5.
Example 20 synthesis of N- (4-methylphenyl) benzamide 3 h: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N- (4-methylphenyl) hydroxylamine (0.36 mmol, 0.044 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was evaporated off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were added, after stirring for 3 hours at room temperature, 1N HCl solution was added to quench the reaction, followed by extraction with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =19 column chromatography 1 gave N- (4-methylphenyl) benzamide in 61% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.87 (d, J = 7.5 Hz, 2H), 7.75 (s, 1H), 7.56-7.47 (m, 5H), 7.18 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H).
13 C NMR (126 MHz, CDCl 3 ) δ 165.6, 135.3, 135.1, 134.3, 131.8, 129.6, 128.8, 127.0, 120.2, 20.9.
Example 21 synthesis of ethyl 4-benzamidobenzoate 3 i: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and ethyl 4- (hydroxyamino) benzoate (0.36 mmol, 0.065 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was evaporated off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added sequentially, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL), after stirring at room temperature for 6 hours, 1N HCl solution was added to quench the reaction, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave ethyl 4-benzoylaminobenzoate in 78% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 8.15 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.75 (q, J = 7.5, 14.5 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H).
13 C NMR (126 MHz, CDCl 3 ) δ 166.2, 142.1, 134.5, 132.2, 131.5, 130.8, 128.8, 127.1, 126.2, 119.2, 60.9, 14.3.
Example 22 synthesis of N- (4-bromophenyl) benzamide 3 j: benzaldehyde (0.36 mmol, 0.038 g, 1 equiv.) and N- (4-bromophenyl) hydroxylamine (0.36 mmol, 0.068 g, 1 equiv.) were dissolved in dichloromethane (2.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were quenched after stirring for 2 hours at room temperature, 1N HCl solution was added, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =20 column chromatography 1 gave N- (4-bromophenyl) benzamide in 88% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.86 (d, J = 7.0 Hz, 2H), 7.80 (s, 1H), 7.58-7.55 (m, 3H), 7.49 (t, J = 9.5 Hz, 4H).
13 C NMR (126 MHz, CDCl 3 )δ 165.6, 137.0, 134.6, 132.1, 128.9, 127.0, 121.7, 117.2.
Example 23 synthesis of 2-chloro-N- (4-chlorophenyl) benzamide 3 k: 2-chlorobenzaldehyde (0.36 mmol, 0.051 g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.36 mmol, 0.052 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL), stirred at room temperature for 5 hours, 1N HCl solution was added to quench the reaction, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =15 column chromatography 1 gave 2-chloro-N- (4-chlorophenyl) benzamide in 89% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.75 (dd, J = 7.5, 1.5 Hz, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.46-7.36 (m, 3H), 7.34 (d, J = 9.0 Hz, 2H).
13 C NMR (126 MHz, CDCl 3 )δ 164.4, 136.1, 134.8, 131.9, 130.6, 130.5, 130.4, 129.9, 129.1, 127.4, 121.4.
Example 24 Synthesis of 4-chloro-N- (4-chlorophenyl) benzamide 3 l: 4-chlorobenzaldehyde (0.36 mmol, 0.051 g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.36 mmol, 0.052 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL), after stirring at room temperature for 1.5 hours, 1N HCl solution was added to quench the reaction, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =20 column chromatography 1 gave 4-chloro-N- (4-chlorophenyl) benzamide in 74% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.80 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H).
13 C NMR (126 MHz, CDCl 3 )δ 164.6, 138.4, 136.2, 133.0, 129.8, 129.3, 129.2, 129.1, 128.4, 121.5.
Example 25 synthesis of 4-trifluoromethyl-N- (4-methylphenyl) benzamide 3 m: 4-trifluoromethylbenzaldehyde (0.36 mmol, 0.063 g, 1 equiv.) and N- (4-methylphenyl) hydroxylamine (0.36 mmol, 0.044 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were stirred at room temperature for 5 hours, 1N HCl solution was added to quench the reaction, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =19 column chromatography 1 gave 4-trifluoromethyl-N- (4-methylphenyl) benzamide in 71% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.98 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 164.3, 138.4, 134.9, 134.8, 129.7, 127.5, 125.9 (q, J C-F = 3.7 Hz), 120.4, 20.9; 19 F NMR (471 MHz, CDCl 3 ) δ -62.96.
Example 26 synthesis of 4-trifluoromethyl-N- (4-chlorophenyl) benzamide 3N: 4-trifluoromethylbenzaldehyde (0.36 mmol, 0.063 g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.36 mmol, 0.052 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.36 mmol, 0.11 g, 1 equiv.) was added in sequence, potassium hydroxide (0.36 mmol, 0.020 g, 1 equiv.) and acetonitrile (2.0 mL) were quenched by stirring at room temperature for 5 hours, 1N HCl solution was added, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =19 column chromatography 1 gave 4-trifluoromethyl-N- (4-chlorophenyl) benzamide in 75% yield.
Of compound 3n 1 H NMR and 13 c NMR is shown in FIG. 3~4.
1 H NMR (500 MHz, CDCl 3 ) δ 7.96 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H).
13 C NMR (126 MHz, CDCl 3 )δ 164.4, 137.9, 136.0, 133.7 (q, J C-F = 33.0 Hz), 130.1, 129.2, 127.5, 125.9 (q, J C-F = 3.8 Hz), 123.5 (q, J C-F = 273.2 Hz), 121.6.
19 F NMR (471 MHz, CDCl 3 ) δ -63.02.
Example synthesis of 3-methoxy-N-phenylbenzamide 3 o: 3-methoxybenzaldehyde (0.73 mmol, 0.10 g, 1 equiv.) and N-phenylhydroxylamine (0.73 mmol, 0.080 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.73 mmol, 0.23 g, 1 equiv.) was added in this order, potassium hydroxide (0.73 mmol, 0.041 g, 1 equiv.) and acetonitrile (5.0 mL) were stirred at room temperature for 2 hours, the reaction was quenched with 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave 3-methoxy-N-phenylbenzamide in 63% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.43 (s, 1H), 7.39-7.34 (m, 4H), 7.15 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 3.84 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 165.6, 159.9, 137.9, 136.4, 129.7, 129.0, 124.6, 120.2, 118.7, 118.0, 112.4, 55.4.
Example 28 synthesis of 3-methyl-N- (4-methylphenyl) benzamide 3 p: 3-methylbenzaldehyde (0.67 mmol, 0. g, 1 equiv.) and N- (4-methyl) phenylhydroxylamine (0.67 mmol, 0.083 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.67 mmol, 0.21 g, 1 equiv.) was added in sequence, potassium hydroxide (0.67 mmol, 0.038 g, 1 equiv.) and acetonitrile (5.0 mL) were stirred for 2.5 hours at room temperature, 1N HCl solution was added to quench the reaction, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave 3-methyl-N- (4-methylphenyl) benzamide in 70% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.51-7.46 (m, 3H), 7.43 (s, 1H), 7.35 (t, J= 7.5 Hz, 1H), 7.27-7.23 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 2.50 (s, 3H), 2.34 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 167.9, 136.4, 135.4, 134.2, 131.2, 130.2, 129.6, 126.6, 125.9, 119.9, 20.9, 19.8.
Example 29 Synthesis of N- (4-chlorophenyl) -2-methylbenzamide 3 q: 2-methylbenzaldehyde (0.24 mmol, 0.029g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.24 mmol, 0.034 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred overnight at room temperature, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.24 mmol, 0.076 g, 1 equiv.) was added in sequence, potassium hydroxide (0.24 mmol, 0.013 g, 1 equiv.) and acetonitrile (3.0 mL) were quenched by stirring at room temperature for 4 hours, 1N HCl solution was added, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave N- (4-chlorophenyl) -2-methylbenzamide in 67% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.56 (d, J = 7.0 Hz, 3H), 7.45 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.27-7.23 (m, 2H), 2.48 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 168.0, 136.5, 136.0, 131.3, 130.5, 129.5, 129.2, 129.1, 126.6, 125.9, 121.1, 19.8.
Example 30 synthesis of 2-methyl-N-phenylbenzamide 3 r: dissolving 2-methylbenzaldehyde (0.28 mmol, 0.034 g, 1 equiv.) and N-phenylhydroxylamine (0.28 mmol, 0.031 g, 1 equiv.) in dichloromethane (3.0 mL), stirring overnight at room temperature, distilling off the solvent, adding tetrabutylammonium fluoride trihydrate (0.28 mmol, 0.088 g, 1 equiv.) in this order, potassium hydroxide (0.28 mmol, 0.016 g, 1 equiv.) and acetonitrile (3.0 mL), stirring at room temperature for 5 hours, adding 1N HCl solution to quench the reaction, extracting with ethyl acetate 3 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, petroleum ether: ethyl acetate =10 column chromatography 1 gave 2-methyl-N-phenylbenzamide in 66% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.61 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 9.0 Hz, 3H), 7.26-7.22 (m, 2H), 7.15 (t, J= 7.5 Hz, 1H), 2.49 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 168.1, 138.0, 136.4, 131.2, 130.3, 129.1, 126.6, 125.9, 124.5, 119.9, 19.8.
Example 31 synthesis of 4-methyl-N-phenylbenzamide 3 s: 4-methylbenzaldehyde (0.83 mmol, 0.10 g, 1 equiv.) and N-phenylhydroxylamine (0.83 mmol, 0.091 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.83 mmol, 0.26 g, 1 equiv.) was added in this order, potassium hydroxide (0.83 mmol, 0.046 g, 1 equiv.) and acetonitrile (5.0 mL) were stirred at room temperature for 3 hours, the reaction was quenched with 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave 4-methyl-N-phenylbenzamide in 68% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.85 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 2.42 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 165.7, 142.3, 138.0, 132.1, 129.4, 129.0, 127.0, 124.4, 120.2, 21.5.
Example synthesis of 3-methyl-N-phenylbenzamide 3 t: 3-methylbenzaldehyde (0.67 mmol, 0.081 g, 1 equiv.) and N-phenylhydroxylamine (0.67 mmol, 0.073 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.67 mmol, 0.22 g, 1 equiv.) was added in this order, potassium hydroxide (0.67 mmol, 0.038 g, 1 equiv.) and acetonitrile (5.0 mL) were quenched by stirring at room temperature for 2.5 hours, 1N HCl solution was added, extraction was then performed 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =13 column chromatography 1 gave 3-methyl-N-phenylbenzamide in 65% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.68-7.64 (m, 4H), 7.38-7.34 (m, 4H), 7.15 (t, J = 7.5 Hz, 1H), 2.41 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 166.0, 138.6, 138.0, 135.0, 132.5, 129.0, 128.6, 127.8, 124.5, 123.9, 120.2, 21.3.
Example 33 synthesis of 2-chloro-N-phenylbenzamide 3 u: 2-chlorobenzaldehyde (0.70 mmol, 0.099 g, 1 equiv.) and N-phenylhydroxylamine (0.70 mmol, 0.076 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.70 mmol, 0.22 g, 1 equiv.) was added in this order, potassium hydroxide (0.70 mmol, 0.039 g, 1 equiv.) and acetonitrile (5.0 mL) were stirred at room temperature for 3.5 hours, 1N HCl solution was added to quench the reaction, followed by extraction with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave 2-chloro-N-phenylbenzamide in 73% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.46-7.35 (m, 5H), 7.17 (t, J = 7.5 Hz, 1H).
13 C NMR (126 MHz, CDCl 3 )δ 164.5, 137.5, 135.2, 131.7, 130.6, 130.4, 130.3, 129.1, 127.3, 124.9, 120.1.
Example 34 Synthesis of N-phenyl-1-naphthamide 3 v: 1-naphthaldehyde (0.67 mmol, 0.105 g, 1 equiv.) and N-phenylhydroxylamine (0.67 mmol, 0.073 g, 1 equiv.) were dissolved in dichloromethane (5.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.67 mmol, 0.21 g, 1 equiv.) was added in sequence, potassium hydroxide (0.67 mmol, 0.038 g, 1 equiv.) and acetonitrile (5.0 mL) were stirred at room temperature for 2.5 hours, the reaction was quenched by adding 1N HCl solution, extracted with ethyl acetate 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave N-phenyl-1-naphthamide in 69% yield.
Of Compound 3v 1 H NMR and 13 c NMR is shown in FIG. 5~6.
1 H NMR (500 MHz, CDCl 3 ) δ 8.35-8.33 (m, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.90-7.88 (m, 1H), 7.80 (s, 1H), 7.71-7.67 (m, 3H), 7.57-7.53 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H).
13 C NMR (126 MHz, CDCl 3 )δ 167.5, 138.0, 134.4, 133.7, 131.0, 130.0, 129.1, 128.4, 127.3, 126.6, 125.2, 125.1, 124.7, 124.6, 120.0.
Example 35 Synthesis of N- (4-chlorophenyl) -4-methylbenzamide 3 w: 4-methylbenzaldehyde (0.24 mmol, 0.029g, 1 equiv.) and N- (4-chlorophenyl) hydroxylamine (0.24 mmol, 0.034 g, 1 equiv.) were dissolved in dichloromethane (3.0 mL), stirred at room temperature overnight, the solvent was distilled off, tetrabutylammonium fluoride trihydrate (0.24 mmol, 0.076 g, 1 equiv.) was added sequentially, potassium hydroxide (0.24 mmol, 0.013 g, 1 equiv.) and acetonitrile (3.0 mL) were added sequentially, stirred at room temperature for 6.5 hours, the reaction was quenched with 1N HCl solution, extracted 3 times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, petroleum ether: ethyl acetate =10 column chromatography 1 gave N- (4-chlorophenyl) -4-methylbenzamide in 78% yield.
1 H NMR (500 MHz, CDCl 3 ) δ 7.78 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).
13 C NMR (126 MHz, CDCl 3 )δ 165.6, 142.6, 136.6, 131.7, 129.5, 129.4, 129.1, 127.0, 121.3, 29.7。
Claims (10)
1. A method for synthesizing N-substituted aryl formamide is characterized in that: dissolving substrate aromatic aldehyde and hydroxylamine in a solvent A, stirring overnight at room temperature, and distilling off the solvent A; adding an accelerator, alkali and a solvent B into the mixture, stirring the mixture at room temperature for reaction for 2 to 46 hours, adding a 1N HCl solution into the mixture for quenching reaction, and finally sequentially extracting, drying, filtering, concentrating and carrying out column chromatography separation to obtain the compound with the structural formula shown in the specification
The target product of (1) is an N-substituted aryl formamide; wherein: r is 1 Is any one functional group of hydrogen, chlorine, methyl, methoxy, nitro, trifluoromethyl and cyano, R 2 Is any one functional group of hydrogen, chlorine, methyl, ester group, carbonyl, bromine and fluorine; the molar ratio of the aromatic aldehyde to the hydroxylamine to the accelerator to the alkali is 1:1 to 1.2:0.5 to 1.5:0.5 to 1.5.
2. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the aromatic aldehyde is one of benzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 2-nitrobenzaldehyde, 3-chlorobenzaldehyde, 2-chlorobenzaldehyde, 4-trifluoromethylbenzaldehyde, 3-methoxybenzaldehyde, 3-methylbenzaldehyde, 2-methylbenzaldehyde, 4-methylbenzaldehyde and 1-naphthaldehyde.
3. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the hydroxylamine is one of N-phenylhydroxylamine, 4-chlorphenylhydroxylamine, 3-methylphenylhydroxylamine, 4-bromophenylhydroxylamine and 4-ethylhydroxylamine-benzoate.
4. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the solvent A is any one of chloralkane solvent, alcohol and ether solvent.
5. The method of claim 4 for the synthesis of an N-substituted aryl carboxamide, wherein: the chloralkane solvent is any one of chloroform, dichloromethane and carbon tetrachloride.
6. The method of claim 4 for the synthesis of an N-substituted aryl carboxamide, wherein: the alcohol solvent is any one of methanol, ethanol and isopropanol.
7. The method of claim 4 for the synthesis of an N-substituted aryl carboxamide, wherein: the ether solvent is any one of diethyl ether, tetrahydrofuran and 1,4-dioxane.
8. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the accelerant is any one of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, cesium fluoride and potassium fluoride.
9. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the alkali is any one of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, DMAP and DBU.
10. The method of claim 1 for the synthesis of an N-substituted aryl carboxamide, wherein: the solvent B refers to a nitrile solvent.
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